The emergence of antibiotic-resistant Staphylococcus aureus has created an urgent need for new therapeutic approaches to treat the variety of diseases caused by this common pathogen. S. aureus damages host tissues by the secretion of a variety of toxic exomolecules known as virulence factors. The expression of these factors is controlled by an autocrine regulatory system whereby bacteria secrete autoinducing pheromone peptides that act on the cell to upregulate expression of the set of genes encoding virulence factors. This proposal is based on the serendipitous discovery of a modified peptide contaminating a batch of synthetic pheromone peptide based on the sequence of a non- pathogenic strain of Staphylococcus. This peptide, called virulence inhibitory factor (VIF), inhibited synthesis of alpha toxin and toxic shock syndrome toxin in all Staphylococcal strains tested. Further studies revealed that small molecule analogs of VIF inhibited virulence factor production in vitro and protected mice from a lethal systemic S. aureus infection. The goal of this proposal is to evaluate a large panel of small VIF analogs in vitro and select the best drug candidate for further studies in vivo. Proposed studies include pharmacology, toxicology, and various animal models of S. aureus infection in preparation of an IND. This novel therapeutic approach has promise in the treatment of antibiotic-resistant Staphylococci. PROPOSED COMMERCIAL APPLICATIONS: Due to the emergence of drug-resistant strains of Staphylococci, many infections are not treatable with conventional antibiotics. The pathogenesis of Staph. infections depend on the production of virulence factors that promote bacterial colonization and are toxic to the host tissues. The present application proposes to develop a novel drug that inhibits production of virulence factors and should be therapeutic to antibiotic resistant Staph.